Project Summary This is an application for a K23 award for Dr. Rachel Rutishauser, MD, PhD, a fellow in Infectious Diseases at the University of California, San Francisco who is establishing herself as a young investigator in patient- oriented studies of HIV immunology. Her goal is to apply her PhD graduate school background in basic CD8+ T cell biology to study the mechanisms that underlie protective and dysfunctional immune responses in HIV infection. Nearly forty million people worldwide are infected with HIV and identifying interventions to induce HIV remission or cure is an NIH high priority research area. Many approaches propose to do so by eliciting protective HIV-specific CD8+ T cells. However, in order to be effective, these therapies need to overcome HIV- specific CD8+ T cell exhaustion. Exhaustion is defined as a loss in the regenerative capacity of antigen- specific CD8+ T cells to proliferate and generate functional effector cells. This K23 award will provide Dr. Rutishauser with the support to explore how HIV-specific CD8+ T cell exhaustion is regulated by: (1) memory CD8+ T cell-associated transcriptional programs, (2) tissue microenvironments, and (3) chronic inflammation. Specifically, she will perform phenotypic, functional, and single-cell transcriptomic analysis of HIV-specific MHC Class I tetramer+ CD8+ T cells from the peripheral blood, lymph node, and gut tissue of thirty HIV- infected individuals who she will recruit from the UCSF-based SCOPE cohort from three clinical groups: individuals who naturally control infection (controllers), as well as non-controllers on and off of antiretroviral therapy (ART). She will also determine if reducing chronic inflammation can enhance HIV-specific CD8+ T cell function by leveraging peripheral blood samples from an ongoing NIH-funded clinical study (NCT02272946) of ART-suppressed HIV-infected individuals who are administered the IL-1? inhibitor, canakinumab. To achieve these goals, Dr. Rutishauser will be co-mentored by Dr. Peter Hunt, an HIV translational immunologist and expert in the mechanisms of HIV immune activation, Dr. Joseph Mike McCune, a laboratory-based scientist who has made several fundamental discoveries about HIV pathogenesis, Dr. Steven Deeks, a leader in the HIV cure field, and Dr. Mark Ansel, an immunologist with expertise in T cell differentiation. Through a focused program of mentored training and coursework, the candidate will develop advanced skills in clinical research, human translational immunology, and single-cell transcriptional analysis. The results of these studies are anticipated to be directly relevant to HIV cure research and widely applicable to developing treatments for other disease states in which exhausted antigen-specific CD8+ T cells arise, such as other chronic infections and cancer. Ultimately, the training and research plans outlined here will support Dr. Rutishauser as she transitions from being a basic immunologist and clinical infectious disease specialist to being a translational researcher equipped with the skills to pursue an independent career focused on elucidating the fundamental principles of CD8+ T cell biology and informing the development of therapeutics and vaccines for infectious diseases.